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Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients

  • Original Articles
  • 5-Fluorouracil, Circadian Infusion, Chronobiology
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Abstract

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9–10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3–4 a.m. The peak drug delivery was shifted to 9–10 p.m. in all patients developing toxicity of ≥grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m2 daily) and LV (5 mg/m2 daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m2 daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3–4 a.m. than was possible with a flat infusion of these drugs. Toxicity was redouced even further with peak drug delivery at around 9–10 p. m. The recommended dose for phase II studies using this schedule is 250 mg/m2 5-FU daily and 20 mg/m2 LV daily with the peak of the infusion occurring at 9–10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.

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Authors and Affiliations

  1. Division of Medical Oncology, Toronto Bayview Regional Cancer Center, University of Toronto, 2075 Bayview Avenue, M4N 3M5, North York, Ontario, Canada

    Georg A. Bjarnason, Ian G. Kerr, Nancy Doyle, Moira Macdonald & Marcia Sone

  2. Division of Clinical Pharmacology, Sunnybrook Health Science Center, Department of Medicine, University of Toronto, 2075 Bayview Avenue, M4N 3M5, North York, Ontario, Canada

    Georg A. Bjarnason, Ian G. Kerr, Nancy Doyle, Moira Macdonald & Marcia Sone

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  1. Georg A. Bjarnason
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  2. Ian G. Kerr
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  3. Nancy Doyle
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  4. Moira Macdonald
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Additional information

This work was supported in part by a grant from Lederle Laboratories Division, Cyanamid Canada Inc. This paper was presented in part in abstract form (abstract 528) at the 6th European Conference on Clinical Oncology and Cancer Nursing, October 27–31, 1991, Florence, Italy

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Bjarnason, G.A., Kerr, I.G., Doyle, N. et al. Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients. Cancer Chemother. Pharmacol. 33, 221–228 (1993). https://doi.org/10.1007/BF00686220

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  • DOI: https://doi.org/10.1007/BF00686220

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